Medical Device Daily Washington Editor

GAITHERSBURG, Maryland – Tuesday evening, Inamed (Santa Barbara, California) fell oh-so-short in its attempt to convince an FDA panel to lift the agency’s 13-year-old ban on silicone-gel breast implants.

In a 5-4 vote, the General and Plastic Surgery Devices Panel of the FDA’s Center for Devices and Radiological Health decided against recommending approval of Inamed’s implants, citing concerns about long-term data and unanswered questions concerning device breakage.

Greeting the vote was loud applause, coming from those who had provided heated testimony objecting to put- ting the implants back on the market.

Inamed appeared before this panel in late 2003 – the current panel membership now slightly different – getting a 9-6 vote to recommend commercialization. But that panel attached a laundry list of conditions (Medical Device Daily, Oct. 17, 2003), and the agency then turned down its premarket approval application (PMA) (MDD, Jan. 9, 2004). That turndown was accompanied by tougher standards for evaluation of the devices.

Dan Cohen, Inamed’s vice president of global government affairs, told reporters following the panel’s vote that he was disappointed by the panel vote but that the company will continue to work with the agency to win approved. He declined to predict a timeframe for re-filing of the application.

“The core study continues,” he said. “That’s our commitment.”

During its presentation, Inamed maintained that its third-generation line of products is superior to earlier iterations of gel implants from the 1970s and 1980s, and that it had increased its study data since 2003, sufficient to satisfy the FDA.

The agency placed a ban on silicone implants in 1992, due to fears that device leakage was causing serious illnesses, such as lupus, rheumatoid arthritis, even cancer. Silicone-gel implants first entered the market in 1962, prior to the need for proving to the FDA safety and effectiveness.

While many studies support the contention that the devices do not lead to disease, a differing stew of data and statistical models – offered by the FDA and Inamed presentations – and unclear information on rupture rates and possible effects, served to puzzle and confuse the panelists.

Based on a risk/benefit approach, “The benefits outweigh the risks,” said Patricia Walker, MD, PhD, Inamed’s executive vice president for R&D. “The risks are those of surgery and local complications and the potential for additional surgeries, but the benefits are numerous.”

Gel implants offer more options for patients and physicians, have a more natural appearance and feel more like normal breast tissue with “no increased risk over saline,” Walker said.

Another major obstacle for panel members was that the company said it already planned to redesign one of the newer models of implants under consideration in its PMA, Style 153. Style 153 has a teardrop shape and the gel is contained within in a pocket toward the bottom edge of the implant. A redesign would place the pocket of silicone gel away from the implant wall, providing a more even protective barrier around the gel.

“I have very significant concerns about 153 and approving a model that is about to change,” said Joseph LoCicero III, MD, professor and chairman of the department of surgery at the University of South Alabama (Mobile). “We have evidence for safety for the other devices, but apparently ruptures occur with 153 and particularly in patients who are being reconstructed. I’m not sure the same safety profile exists.”

About half of the ruptures documented by the company in its three-year data occurred with Style 153.

“We are talking about big, big numbers of people who will take advantage of the availability of these devices,” said panel member Amy Newburger, MD, a dermatologist from Scarsdale, New York. “With the exception of 153, I feel comfortable with the safety data of the two- to three-year term, but I think longer follow-up is really needed. I am not comfortable with safety beyond three years.”

Many patients do not realize their implants have ruptured, and they may go a long time without the symptoms of a rupture, which is called the silent rupture rate. According to Inamed, 86% of patients with a rupture are not aware of it.

Inamed also presented only three years of screening information and had to estimate possible 10-year outcomes.

“I think the data are lacking; therefore I cannot answer the question about whether there is a reasonable assurance that the device is safe because there is a big part of the data that hasn’t been analyzed correctly yet,” said Brent Blumenstein, PhD, a statistician with TriArc Consulting (Seattle).

Early in the meeting during a discussion of the Ina-med’s 10-year safety projections, Blumenstein pulled no punches, calling some of the company’s statistical modeling “unimaginative, incomplete and poorly managed.”

Stephen Li, PhD, president of Medical Device Testing and Innovations (Sarasota, Florida), appeared to express the quandary of many panelists. “I am in a little personal agony,” Li said. “My ‘no’ is perhaps the weakest of no’s, and I think in October of 2003 I perhaps had the weakest of yes’s. I am really on the fence about this.”

He said that, with more data, he would have voted “un-equivocally” for approval and that the FDA should continue to allow implant use in reconstruction and revision.

During the company’s testimony, Li continually questioned its breakage data. “We really do not know why this device is failing when it fails,” he said.

Inamed has said that most of the ruptures reported in their PMA application were caused by an instrument – for example, a scalpel – during implantation.

Li noted data indicating that the implants did not break even with intense weight testing after being punctured with a pushpin. “That is a tribute to the viscosity of the gel and the strength of the device,” he said, and that a doctor would have “to work at it” with a scalpel to do the damage cited.

“But,” he added, “what’s good about that is what’s bad about it. There may be something else causing rupture.”

Li concluded: “If I had better information about the mechanism of failure, I could go along with it. But I need more data. If you come back with five-year data and it looks as good as this, then you’ve got my yes.”

For some panel members, the choice was a difficult mix of raw data and caregiver compassion.

“I am one of the few people on the panel for whom care of these women is not a theoretical construct,” said Michael Miller, MD, professor and deputy chairman of the department of plastic surgery at MD Anderson Cancer Center (Houston). “For 15 years I have cared for them. I insert these devices; I care for the complications; and I am intimately familiar with all the issues in addition to the data. More data is only going to help us to understand this better.”

Cheryl Ewing, MD, assistant professor of clinical surgery at the Carol Buck Breast Care Center at the University of California, San Francisco, said she believed Inamed had “adequately addressed” the safety issues, and she voted against a motion not to approve. “As a clinician, I am somewhat disappointed,” she said of the panel’s final decision.

Leigh Callahan, PhD, associate professor of orthopedics, medicine and social medicine at the University of North Carolina (Chapel Hill), said, “This is a risk/benefit issue, and although I am not comfortable with all the data presented in this particular study, I think I would have felt comfortable for this to be available for women to have a choice.”

The panel’s decision will not affect the company’s impending purchase by Medicis (Scottsdale, Arizona), Cohen told reporters, that deal valued at nearly $2.8 billion (MDD, March 22, 2005).

“The merger was not about the next several weeks, it was about the next several years,” he said. “Both companies have products in the pipeline, and there is no time base for when any particular product will be approved, so we do not anticipate that will have any impact on the merger.”